EMA/285771/2015 Summary of the risk management plan (RMP) for Opdivo (nivolumab) This is a summary of the risk management plan (RMP) for Opdivo, which details the measures to be taken in order to ensure that Opdivo is used as safely as possible. For more information on RMP summaries, see here. This RMP summary should be read in conjunction with the EPAR summary and the product information for Opdivo, which can be found on Opdivo s EPAR page. Overview of disease epidemiology Opdivo is a medicine which contains the active substance nivolumab. It is used to treat melanoma (a type of skin cancer) that has metastasised (spread to other parts of the body) or cannot be surgically removed. The number of people diagnosed with this cancer is increasing worldwide. In 2008, around 69,000 new melanomas occurred in 27 European countries. In about 6 out of 100 newly-diagnosed cases, the melanoma is inoperable or has metastasised. This suggests that newly-diagnosed inoperable or metastatic melanomas in these 27 European countries number over 4,000 per year. Summary of treatment benefits Opdivo has been shown to be effective in treating patients with advanced malignant melanoma (melanoma that could not be treated by surgery or had spread throughout the body) in two main studies. The first study looked at 418 previously untreated advanced melanoma patients who received either Opdivo or a standard cancer medicine (dacarbazine). The study found that patients treated with Opdivo survived longer (on average for over 14 months) than patients who received dacarbazine (around 12 months). The second study looked at 405 advanced melanoma patients whose disease had got worse despite previous treatment with a standard cancer medicine. Patients were given Opdivo or the investigator s choice of cancer treatment (dacarbazine or a combination of carboplatin and paclitaxel). In this study, where patients were followed up for at least 6 months, around 32% (38 out of 120) of patients given Opdivo responded to treatment and had a reduction in their tumours compared with about 11% (5 out of 47) of patients given investigator s choice of treatment. Unknowns relating to treatment benefits The benefits of Opdivo on its own or in combination in previously untreated patients or in those who did not respond to previous treatment are still being studied. Studies in children are also being carried out. Page 1/8
Summary of safety concerns Important identified risks Risk What is known Preventability pneumonitis (lung inflammation resulting from activity of the immune system) colitis (inflammation of the gut resulting from activity of the immune system) hepatitis (liver inflammation resulting from activity of the immune system) Opdivo increases the risk of lung inflammation. In clinical trials, between 2 and 3 patients in 100 developed lung inflammation, sometimes fatal. Signs or symptoms may include dry cough and shortness of breath. Nivolumab increases the risk of diarrhoea or colitis. In nivolumab clinical trials, 17 patients in 100 developed diarrhoea or colitis. Signs and symptoms may include watery, loose or soft stools, an increased number of bowel movements, blood in stools or dark-coloured stools and pain or tenderness in the stomach area. Nivolumab increases the risk of hepatitis. In nivolumab clinical trials, between 3 and 8 patients in 100 had abnormal liver tests. Signs and symptoms of hepatitis may include eye or skin yellowing (jaundice), pain on the right side of the stomach area and tiredness. In the event of lung inflammation, doctors might consider stopping treatment with Opdivo temporarily or permanently, depending on the severity. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may prevent serious complications such as respiratory failure. Patients will be provided with an alert card warning them of the risk of lung inflammation and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. In the event of diarrhoea or colitis, doctors might consider stopping treatment with Opdivo temporarily or permanently, depending on the severity. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may prevent serious complications such as gut perforation (developing a hole in the wall of the gut) or severe colitis requiring colectomy (surgery to remove a part of the gut). Patients will be provided with an alert card warning them of the risk of gut inflammation and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Patients should be monitored for signs and symptoms of hepatitis such as an increase in blood levels of transaminases and total bilirubin levels. In the event of abnormal liver enzyme tests, doctors might consider stopping treatment with Opdivo temporarily or permanently. Prompt review of blood tests, recognition of signs and symptoms and implementation of the recommended management guidelines may prevent serious complications. Patients will be provided with an alert Page 2/8
Risk What is known Preventability nephritis (kidney inflammation) or kidney problems resulting from activity of the immune system endocrinopathies (problems with hormone producing organs resulting from activity of the immune system) rash Nivolumab increases the risk of kidney inflammation. In nivolumab clinical trials, 2 patients in 100 developed kidney inflammation. Signs or symptoms may include production of smaller amounts of urine. Nivolumab increases the risk of inflammation of hormone-producing glands (thyroid, adrenal, or pituitary glands) and may affect how these glands work. In nivolumab clinical trials, 9 patients in 100 developed disorders of hormone-producing glands. Signs or symptoms of endocrine gland problems may include headaches, tiredness and weight changes. Nivolumab increases the risk of rash. In the clinical trials, between 35 and 41 patients in 100 developed rash. Signs or symptoms of severe skin reaction may include skin rash with or without itching, peeling of the skin, and dry skin. card warning them of the risk of hepatitis and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Patients should be monitored for signs and symptoms of kidney problems. In the event of nephritis or kidney dysfunction, doctors might consider stopping treatment with Opdivo temporarily or permanently. Prompt recognition of signs and symptoms, prompt review of blood tests and implementation of the recommended management guidelines may prevent serious complications. Patients will be provided with an alert card warning them of the risk of kidney problems and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Patients should be monitored for signs and symptoms of endocrinopathies. In the event of an endocrinopathy, treatment with Opdivo should be stopped temporarily or permanently. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may prevent serious complications such as adrenal crisis. Patients will be provided with an alert card warning them of the risk of endocrine gland problems and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Early detection and timely treatment are key to recovery and to prevent severe complications. Patients will be provided with an alert card warning them of the risk of skin problems and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Physicians may start treatment with corticosteroids (in order to prevent more severe complications and reduce the Page 3/8
Risk What is known Preventability Other immunerelated adverse reactions Severe infusion reactions Other selected immune-related adverse reactions, which are uncommon but considered important identified risks, include uveitis (inflammation of the middle layer of the eye), pancreatitis (inflammation of the pancreas), demyelination (loss of the protective layer surrounding certain nerve cells), Guillain-Barré syndrome (a nerve disorder that can result in pain, numbness, muscle weakness and difficulty walking), and myasthenic syndrome (another disorder resulting in muscle weakness). These immune-related adverse reactions can be serious and lifethreatening. Severe reactions to infusion (drip) of Opdivo into a vein were observed in clinical trials (in between 1 and 7 patients in 100). Serious acute infusion reactions were infrequent. However, life-threatening reactions may occur. Signs or symptoms may include throat or chest tightness, wheezing, skin rash or hives, dizziness, or lightheadedness. symptoms). If skin reactions occur, doctors may manage them with corticosteroids; treatment with Opdivo may be stopped temporarily or permanently depending on the severity. If immune-related adverse reactions are suspected, adequate evaluation should be performed. Based on the severity of the adverse reactions, Opdivo should be temporarily stopped and corticosteroids (anti-inflammatory medicines) administered. Upon improvement, Opdivo may be resumed after corticosteroid taper. Opdivo must be permanently stopped if any severe immune-related adverse reaction comes back and for any life-threatening immune-related adverse reaction. Patients should not be given Opdivo if they have a history of allergic reactions to nivolumab or any other ingredients. Patients should seek medical attention immediately if they start feeling unwell during or soon after the infusion of Opdivo. Important potential risks Risk Effects on the developing baby (embryofetal toxicity) Development of antibodies (immune What is known Based on its mechanism of action and data from animal studies, nivolumab may cause fetal harm when administered to a pregnant woman. A study in experimental models revealed damaged to the fetus, which suggested that pregnant women exposed to Opdivo may be at risk of losing their fetus in the third trimester or of giving birth prematurely. Therefore, Opdivo is not recommended in pregnant women, nor in women of childbearing potential not using effective contraception unless the benefit outweighs the potential risks. Effective contraception should be used for at least 5 months following the last dose of Opdivo. Theoretically, immunogenicity may lead to infusion reactions or reduced effectiveness. Although low rates of immunogenicity were seen, no impact has Page 4/8
Risk response) against the medicine (Immunogenicity) Cardiac arrhythmias (heart rhythm problems) What is known been observed on safety or efficacy, even following prolonged dose interruptions and re-administration of the medicine. In a study with previously untreated patients who were not eligible for surgery due to spread of their melanoma the incidence of cardiac arrhythmia with Opdivo was lower than with dacarbazine. However, in another study comparing nivolumab with cancer medicines called anti-ctla4 medicines or BRAF inhibitors, the incidence of arrhythmias was higher in those given nivolumab. Missing information Risk Use in children Severely reduced liver and/or kidney function (severe liver and/or renal impairment) Patients with autoimmune diseases Patients already receiving systemic immunosuppressants (medicines that suppress the immune system) before starting nivolumab What is known The effect of Opdivo in patients below 18 years old is not known. Opdivo should not be used in children below 18 years of age. The effect of Opdivo in patients with severely reduced liver or kidney function has not been studied. Opdivo must be given with caution in patients with moderately or severely reduced liver function. No formal study with Opdivo has been conducted in patients with autoimmune diseases. No formal study has been conducted. Summary of risk minimisation measures by safety concern All medicines have a summary of product characteristics (SmPC) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet. The measures listed in these documents are known as routine risk minimisation measures. The SmPC and the package leaflet are part of the medicine s product information. The product information for Opdivo can be found on Opdivo s EPAR page. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). Full details on these conditions and the key elements of any educational material can be found in Annex II of the product information which is published on Opdivo s EPAR page; how they are implemented in each country however will depend upon agreement between the marketing authorisation holder and the national authorities. Page 5/8
These additional risk minimisation measures are for the following risks: pneumonitis, colitis, hepatitis, nephritis or renal dysfunction, endocrinopathies, rash, and other immune-related adverse reactions Risk minimisation measure: Healthcare professional and patient educational material. Objective and rationale: To ensure that healthcare professionals and patients are aware of these risks and their appropriate management measures. Description: The following educational materials will be provided to physicians and patients who are expected to use Opdivo: adverse reaction management guide, for healthcare professionals, reminding them of the important identified risks related to the immune system, how to recognise these conditions, and their appropriate management. an alert card for patients, warning them of the risks and how to recognise symptoms, and reminding them of the importance of contacting their doctor promptly should these occur or worsen. These communication tools will provide the opportunity for reinforcing key messages about early recognition and appropriate management of important identified risks to maintain a favourable benefitrisk of Opdivo. Planned post-authorisation development plan List of studies in post-authorisation development plan Study/activity (including study number) CA209067: Phase Objectives To compare overall Safety concerns /efficacy issue addressed Clinical efficacy in Status Started Planned date for submission of (interim and) final results Interim CSR 3, randomized, survival. subjects with previously submission: double-blind study untreated, unresectable 3Q2015 / in subjects (non-operable) or Final CSR treated with metastatic (spread) submission: nivolumab melanoma. 1Q2017. monotherapy, ipilimumab monotherapy, and nivolumab combined with ipilimumab. CA209069: Phase To compare Clinical efficacy in Started Final CSR 2, randomized objective response subjects with tumours submission: double blind study rate. that have a wild type 3Q2015. in subjects (WT) BRAF gene (also treated with known as non-mutated, nivolumab the most common form combined with of the gene), who have ipilimumab vs previously untreated Page 6/8
Study/activity (including study number) ipilimumab monotherapy. Objectives Safety concerns /efficacy issue addressed unresectable or metastatic melanoma. Status Planned date for submission of (interim and) final results CA209066: a Phase 3, randomized, double-blind study of nivolumab vs dacarbazine in subjects with BRAF wild type, previously untreated, unresectable or metastatic melanoma. To compare overall survival, progression-free survival, and objective response rate. Clinical efficacy in subjects with tumours that have non-mutated BRAF previously untreated unresectable or metastatic melanoma. Started The final clinical study report should be submitted by 30th June 2016. CA209037: a Phase 3, randomized, open-label study of nivolumab vs investigator s choice in advanced (unresectable or metastatic) melanoma patients progressing post anti-ctla-4 therapy. To compare objective response rate, overall survival, and progression-free survival. Clinical efficacy in subjects with advanced (unresectable or metastatic) melanoma. Started The updated data/study report should be submitted by 31st December 2015. CA209234: Pattern of Use, Safety, and Effectiveness of Nivolumab in Routine Oncology Practice. To assess use pattern, effectiveness, and safety of nivolumab, and management of important identified risks of nivolumab in patients with lung cancer or melanoma in routine oncology practice. Postmarketing use, safety profile, management and outcome of immunerelated pneumonitis, colitis, hepatitis, nephritis or renal dysfunction, endocrinopathies, rash, and other immunerelated adverse reactions (uveitis, pancreatitis, demyelination, Guillain- Barré syndrome, and Planned Final CSR submission: 4Q2024. Page 7/8
Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed myasthenic syndrome), and infusion reactions. Status Planned date for submission of (interim and) final results Studies which are a condition of the marketing authorisation None of the above studies are conditions of the marketing authorization. Summary of changes to the risk management plan over time Not applicable. This summary was last updated in 05-2015. Page 8/8